Glaucoma is a chronic disease characterized by progressive optic nerve damage and vision loss. There is no cure for glaucoma; management of the disease focuses on lowering intraocular pressure which has been effective in reducing the progression of the disease. One therapeutic treatment involves the administration of timolol to reduce the production of aqueous humor by the ciliary epithelium. Unfortunately, the targeted structures are located in remote inner regions of the eye. The traditional mode of topical drug delivery is limited in efficacy by physiological barriers, side effects, and poor patient compliance with the drug regimen. Side effects include but are not limited to severe cardiac effects with beta blocker drops. This proposal investigates a novel method for targeted intraocular delivery of glaucoma medication at therapeutic levels with a microelectromechanical systems (MEMS)-fabricated microfluidic device. This device is implanted in the subconjunctival space and consists of a refillable drug reservoir, electrolysis- actuated pump, transscleral cannula, and flow control valves. The medication contained within the reservoir is driven by the electronically-controlled pump through the flexible transscleral cannula which is directed into the anterior chamber and thereby to the ciliary epithelium - the site of treatment. Directed delivery to intraocular tissues reduces the diffusion distance of the drug, increases the efficacy of each dose, reduces the size of the dose, and reduces the amount of unintended systemic absorption of unused drug and the associated side effects. Furthermore, this platform enables precise temporal and spatial control of ocular drug delivery not possible with conventional methods. Specific Aim 1: Fabrication of a multi-component MEMS drug delivery system for targeted delivery of glaucoma medication. A fully integrated device consisting of an electrolysis pump, drug reservoir, check valve, and cannula will demonstrate controlled and repeatable dosing. Specific Aim 2: Demonstration of implantation and device refillability in ex vivo experiments. Enucleated porcine eyes will be used to develop surgical procedures and device refill techniques. Specific Aim 3: Demonstration of controllable and repeatable delivery of timolol in a rabbit model of glaucoma. The long term biocompatibility and function of devices will be demonstrated and then the device will be implemented in an animal model of glaucoma. Efficacy of the device in managing intraocular pressure will be compared to topically applied timolol. For the effective management of glaucoma, a novel miniaturized drug delivery device will deliver drugs directly into the interior of the eye. This method of delivery will maximize the therapeutic benefits of the drug therapy while minimizing risk to the patient by reducing side effects. The broad drug compatibility and flexibility in implementing the device allow its application to the treatment of other chronic diseases, in particular, diseases associated with vision loss requiring treatment of tissues located in remote inner regions of the eye. [unreadable] [unreadable] [unreadable] [unreadable]